Julius Strauss, MD
Investigators are hopeful that M7824 (MSB0011359C), a bifunctional fusion protein that inhibits the PD-L1 and TGF-β pathways, will improve immune system responses across tumor types. M7824 is composed of an anti-PD-L1 antibody fused to the extracellular domain of TGF-β receptor II, which serves as a “trap” for TGF-β linked to carcinogenesis. Early trial results have been encouraging.
“[M7824] is a drug that is targeting 2 independent aspects of the immune system,” said Julius Strauss, MD, codirector and assistant research physician of the clinical trials group for the Laboratory of Tumor Immunology and Biology at the Center for Cancer Research at the National Cancer Institute. “It’s building off the notable clinical efficacy and responses observed with anti–PD-1 and anti–PD-L1 monoclonal antibodies against a wide array of solid tumors, where patients have had durable objective responses.”
A phase I dose escalation and expansion study of M7824 (NCT02517398) allowed enrollment of patients with metastatic or locally advanced solid tumors, without stratification, and supported selection of a 1200 mg dose administered intravenously every 2 weeks for future clinical studies. The same study has moved into the expansion phase and investigators seek to enroll 587 patients, also with metastatic or locally advanced solid tumors (TABLE).1
M7824 MECHANISM OF ACTION10
CAF indicates cancer-associated fibroblast; EMT, epithelial-mesenchymal transition; NK, natural killer; TAM, tumor-associated macrophage.
PHASE I TRIAL OF M7824 IN PATIENTS WITH SOLID TUMORS10
ECOG indicates Eastern Cooperative Oncology Group.
Patients will be grouped based on their tumor type, with approximately 30 patients in each cohort. Tumor types include non–small cell lung cancer (NSCLC), colorectal cancer (CRC), and gastric cancer, among others. Patients must have an ECOG performance status of 0 or 1, adequate organ function, and no active central nervous system metastases. The primary endpoints vary depending on the cohort. M7824 is composed of a fully human anti–PD-L1 lgG1 monoclonal antibody linked to the 2 extracellular domains of TGF-β receptor II molecules. The TGF-β receptor II portion serves as a trap for all 3 TGF-β isoforms, and by targeting the tumor with the anti-PD-L1 portion, M7824 may reduce the amount of TGF-β within the tumor micro- environment (FIGURE).2-4
“TGF-β is also an immunosuppressive cytokine which [regulates] the T cells in the tumor microenvironment, and blocking it or sequestering it allows for the effector T cells to be reactivated,” Strauss said. The expression of TGF-β receptor on CD8-positive T cells maintains a stimulation threshold that restricts T-cell activation. This threshold is lowered by the suppression of TGF-β signaling, which allows for activation of CD8-positive T-cells against lower-affinity antigens. It is believed that the sequestration of TGF-β isoforms by M7824 thereby increases the diversity of responding CD8-positive T cell clones during the antitumor response.4
“TGF-β also has many other roles in helping tumor growth that can be treated by blocking it and has an important role in epithelial to mesenchymal transition or mesenchymalization of tumor cells, which is a process that makes tumor cells much more resistant to cytotoxic therapies as well as immunotherapies,” Strauss added. Strauss also explained that TGF-β, as part of the mesenchymalization process, can induce metastasis, and when cancer cells are confined to the epithelial phenotype, they are more likely to respond to cytotoxins and immunotherapy and less likely to metastasize. Studies have found that M7824, by targeting TGF-β, has the ability to control mesenchymalization.5
M7824 can also enhance the efficacy of immunotherapy, because it counteracts the TGF-β-mediated differentiation of regulatory T cells and immune tolerance.6
Studies have also shown that M7824 has the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti–PD-L1.7